Project Summary/Abstract Project 2. Overcoming the Tumor Microenvironment. A second major challenge in targeting solid cancers with cellular immunotherapies is the fact that the tumor microenvironment is often immunosuppressed. This type of suppressive microenvironment can prevent immune cell activity, function, expansion and proliferation, even if there are a population of T cells that specifically recognize the tumor. Moreover, there are diverse forms of suppression, and many cases cannot be ameliorated by checkpoint inhibitor treatment. Ultimately, we need to be able to engineer therapeutic T cells that are able to resist or remodel different types of suppressive tumor microenvironments, leading to stronger local proliferation, activation, and persistence of the T cells. Our goals are to develop a number of ways in which to improve T cell efficacy within tumors. Our specific aims are: 1) Engineer synthetic cytokine circuit modules that drive the local expansion/proliferation of therapeutic T cells in tumors. 2) Engineer circuit modules that limit T cell overactivation and exhaustion via regulation or homeostatic feedback control. 3) Engineer synthetic paracrine circuits in which the local delivery of cytokines can systematically remodel the tumor microenvironment. 4) develop a multi-scale computational model to simulate and predict the spatial temporal expansion and activity of engineered therapeutic immune cells in the context of an organism/tumor. This project will provide critical tools to engineer more effective anti-tumor immune cell therapies.